Degradable removable implant for the sustained release of an active compound

ABSTRACT

A degradable, removable, pharmaceutical implant for the sustained release of one or more drugs in a subject, wherein the pharmaceutical implant is composed of a tube comprising an outer wall made of a degradable polymer completely surrounding a cavity, wherein the outer wall has a plurality of openings and wherein the cavity contains one or more sets of micro-particles, which micro-particles contain an active agent or a combination of two or more active agents, and wherein the size of the microparticles is selected such that the majority of the microparticles cannot pass through the openings.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/515,380, filed 12 Jun. 2012, currently pending, which is a nationalstage application of International Application Number PCT/EP2010/070246,filed 21 Dec. 2010, which claims the benefit of U.S. ProvisionalApplication No. 61/288,373, filed 21 Dec. 2009. The entire content ofeach of the aforementioned application is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to an implantable depot polymeric devicethat is easily introduced into the subcutaneous space, removed if thenecessity arises, and degrades when drug delivery function is complete.One or multiple drugs can be incorporated. The device introduces adegree of flexibility where the loading of the drug and polymerproperties selected for the matrix can be individually tailored for thedrug to meet the specific needs of the patient.

BACKGROUND OF THE INVENTION

Implantable drug delivery devices have been known in the art. The deviceis surgically implanted in the body of a human or veterinary patient andthe drug is released in an efficacious manner. Such implantable drugdelivery systems are particularly useful for delivering drugs atsustained rates over extended periods of time. Examples of drug deliveryimplants of this type include Norplant®, Lupron Depot®, and GliadelWafer®.

In the art-known implantable drug delivery systems the active ingredientis embedded in a matrix material that is shaped in a cylindrical form ofsufficient small size to allow subcutaneous implantation via a hollowneedle. A disadvantage associated with such delivery systems is thatthere is a lag time between implantation and delivery of the drugbecause the bodily fluids have to penetrate the implant and startdecomposing the polymeric matrix. This also often leads toirregularities in the release pattern.

Moreover, none such system has been designed to deliver two or moredrugs simultaneously. The utility of an implantable drug delivery systemwould be increased dramatically when this would be made available.Oftentimes a disease state is more efficaciously addressed whentreatment includes two or more active agents that can act together in amore comprehensive, synergistic, or more complimentary fashion. Anexample of this would be the treatment or prevention of infection wheremembers of two different classes of anti-biotics are released from asingle depot system. The activity of each anti-biotic targets differentbacterial strains and in this fashion provides for a more comprehensivetherapy. Another example of utility would be in the delivery of paindrugs. The sustained release of pain medication can provide for longpain-free periods of time for the patient, which is a significantimprovement over the peaks and valleys plasma concentrations of the druginherent in oral therapy. However, the sustained release of multiplepain drugs that have separate mechanisms of action can result insignificantly enhanced pain management.

An even more compelling example for a multi-drug depot can be found inthe treatment of infectious diseases, for example HIV (HumanImmunodeficiency Virus) and HBV (Hepatitis B Virus). Standard therapyfor HIV requires a “cocktail” of at least three drugs. Sustained releasetherapy for HIV can significantly contribute to therapy compliance(reducing pill burden) and reduce the risk of development of resistanceto therapeutic actives. The value for this therapy would increasefurther if the implantable sustained release formulation contained allthe components of the drug cocktail rather than have one sustainedrelease and the others remain as an oral therapy. Other infectiousdiseases that would benefit from this type of therapy are malaria, flu,TB, and Hepatitis C. A multi-drug depot could also be used in apre-exposure setting for high risk populations, for instancepre-exposure prophylaxis for HIV infection.

De-coupling the formulation of the two actives into separate processescan substantially improve stability, increase the drug loading of each,and introduces compositionally flexibility where one drug can beformulated to release faster or slower or one drug is increased ordecreased in dosage depending on the status of the patient.

The ability to remove the device after implantation is important sincemany of the drugs used in the sustained release applications are potentand can cause severe even life-threatening reactions. Even compressingthe microparticles or pellets together into one unit as described in US2001/0026804 does not guarantee that the device is removable since oncethe device is in contact with physiological medium the pellets ormicroparticles will soon separate from one another making it impossibleto completely remove.

US2004/0082937 describes an implantable device for the controlledrelease of a hormone. The device comprises a substrate with a pluralityof reservoirs that each contain a release system that is electricallycontrollable. US2006/0269475 describes a polymer multi-layer structurehaving a predetermined micro-fabricated special pattern comprisingpredetermined reservoirs and channels containing the drug. The polymermulti-layer structure is biodegradable but has a longer lifetime thanthe duration of the therapy that is delivered. The geometrical patternof the polymer structure controls the delivery of the therapy whilepersisting during delivery of the therapy. The device is prepared inlayers that are fused together at elevated temperature, which can causesignificant warping of the reservoir shape leading to significantchanges in the overall loading of the drug in the device or release rateof the drug. Moreover, this void or channel approach to loading thedevice with the drug has a limited capacity for the drug.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1.

Poly(dioxanone) extruded and laser machined tube. Diameter of holes is50 microns, the number of rows of holes is 40, the number of holes perrow is 60. Total number of holes is 2400. Total length of tube is 30 mmand total length of tube containing holes is 20 mm. The internaldiameter of the tube is 3 mm.

FIG. 2.

Cross-section of a poly(dioxanone) tube that has been electrospun. Thewall thickness is 500 microns. The inner diameter is 2 mm.

FIG. 3.

Surface of a poly(dioxanone) tube that has been electrospun. Fibers arerandomly oriented and size of openings formed by fiber network is in therange of 1-20 microns.

FIG. 4.

Optical micrographs of microparticles containing 70% (w/w) TMC278 and30% (w/w) PLGA 50/50 1A. Magnification is 100×.

FIG. 5.

Optical micrograph of microparticles containing 70% (w/w) TMC114 and 30%(w/w) PLGA 50/50 2A. Magnification is 500×.

DESCRIPTION OF THE INVENTION

The present invention relates to a degradable, removable, pharmaceuticalimplant for the sustained release of one or more drugs in a subject,wherein the pharmaceutical implant is composed of a tube comprising anouter wall made of a degradable polymer completely surrounding a cavity,wherein the outer wall has a plurality of openings and wherein thecavity contains one or more sets of micro-particles, whichmicro-particles contain an active agent or a combination of two or moreactive agents, and wherein the size of the microparticles is selectedsuch that the majority of the microparticles cannot pass through theopenings.

The tube is composed of a degradable polymer. The microparticles containan active ingredient or a combination of two or more active ingredientsand are conceived such that they release the active ingredient uponcontact with bodily fluids. The degradable polymer of which the tube ismade is selected such that it does not substantially degrades before therelease of the active ingredient or ingredients from the microparticlesis substantially complete. The selection of the type of microparticlesand their relative amounts are predicated on the specific needs of thepatient subject.

As used herein, the term degradable or biodegradable means degradable bythe subject, in particular animal, more in particular human, carryingthe implant of the present invention. The degradation process in thesubject can be, for example, an enzymatic or hydrolytical process.

In one embodiment the tube contains two or more sets of microparticles,each set containing a different active ingredient. This allows for amulti-depot system where a combination of drugs needs to beadministered. In a specific embodiment the multi-depot system containsat least two, and in particular three, anti-HIV agents and the implantis used in anti-HIV therapy, which is based on the administration of acombination of anti-HIV agents.

Thus, one embodiment of the present invention relates to a degradable,removable, pharmaceutical implant for the sustained release of one drugin a subject, wherein the pharmaceutical implant is composed of a tubecomprising an outer wall made of a degradable polymer completelysurrounding a cavity, wherein the outer wall has a plurality of openingsand wherein the cavity contains one or more sets of micro-particles,which micro-particles contain said drug, and wherein the size of themicroparticles is selected such that the majority of the microparticlescannot pass through the openings. In particular, the cavity contains oneset of microparticles, which micro-particles contain the drug.

One embodiment of the present invention relates to a degradable,removable, pharmaceutical implant for the sustained release of two drugsin a subject, wherein the pharmaceutical implant is composed of a tubecomprising an outer wall made of a degradable polymer completelysurrounding a cavity, wherein the outer wall has a plurality of openingsand wherein the cavity contains two sets of micro-particles, each set ofmicroparticles containing a different drug, and wherein the size of themicroparticles is selected such that the majority of the microparticlescannot pass through the openings.

One embodiment of the present invention relates to a degradable,removable, pharmaceutical implant for the sustained release of two ormore drugs in a subject, wherein the pharmaceutical implant is composedof a tube comprising an outer wall made of a degradable polymercompletely surrounding a cavity, wherein the outer wall has a pluralityof openings and wherein the cavity contains one or more sets ofmicro-particles, which micro-particles contain said drugs, wherein a setof microparticles contains all drugs, contains a combination of two ormore drugs but not all drugs or contains one drug, and wherein the sizeof the microparticles is selected such that the majority of themicroparticles cannot pass through the openings. In one embodiment, whena set of microparticles contain all drugs, then preferably only one setof microparticles is present in the implant. In one embodiment, each setof microparticles contains a different drug.

The wall of the tube contains openings to allow physiological fluid topenetrate the interior cavity thereby allowing the physiological fluidto extract the drug or drugs from the microparticles and additionally tofacilitate the diffusion of the drug-loaded physiological fluid from theinterior of the tube to the exterior. The openings are formed to allowphysiological fluid to penetrate but are too small for themicroparticles to escape from the interior of the tube. Some of themicroparticles may leave the implant but the size of the openings andthe size of the microparticles are designed such that a majority of themicroparticles is locked in the cavity of the implant. A majority of themicroparticles being locked in the cavity of the implant means that atleast 85% (w/w) of the microparticles are locked in the cavity of theimplant; preferably at least 90% (w/w); more preferably at least 95%(w/w); even more preferably at least 98% (w/w) or 99% (w/w) of themicroparticles are locked in the cavity of the implant. In oneembodiment, the size of the microparticles is selected such that themicroparticles cannot pass through the openings.

Where more than one set of microparticles is present, each set ofmicroparticles can be designed to degrade over a range of rates byvarying the polymer properties used in the production of each of themicroparticles in the set. This ensures drug delivery over a sustainedrange of time. The degradation rate of the polymer that composes thecylindrical tube is slower than the rate of degradation of themicroparticles. This ensures that the implant with its contents can beremoved in the case of adverse events.

Hence, the implantable removable degradable implant of the presentinvention functions as a depot system that can deliver one or moreactive ingredients over a sustained period of time. The implant of theinvention is a perforated tube that contains one or more sets ofmicroparticles, each set of microparticles containing one or more activeagents. The selection of the types of actives to be delivered as well asthe rate at which they are delivered can be tailored to the needs of apatient.

The tube that encases the microparticles is composed of a biocompatible,biodegradable polymer. It is necessary to select the material ofcomposition of the tube carefully, such that the tube degrades after themicroparticles degrade. This allows the removal of the drug deliverysystem in the case of an adverse event. Biodegradable polymers readilybreak down into small segments when exposed to moist body tissue. Thesegments then either are absorbed by the body or passed by the body.More particularly, the biodegraded segments do not elicit permanentchronic foreign body reaction, because they are absorbed by the body orpassed from the body, such that no permanent trace or residual of thesegment is retained by the body. Biodegradable polymers can also bereferred to as bioabsorbable polymers and both terms can be usedinterchangeably within the context of the present invention.

Suitable biocompatible, biodegradable polymers comprise aliphaticpolyesters, poly(amino acids), copoly(ether-esters), polyalkyleneoxalates, polyamides, poly(iminocarbonates), poly(orthoesters),polyoxaesters, polyamidoesters, polyoxaesters containing amine groups,poly(anhydrides), polyphosphazenes, and blends thereof. For the purposeof this invention aliphatic polyesters include but are not limited tohomopolymers and copolymers of lactide (which includes d-, l-, and mesolactic acid, and d-, l-, and meso lactide), glycolide (includingglycolic acid), epsilon-caprolactone, p-dioxanone (1,4-dioxan-2-one),and trimethylene carbonate. In one embodiment, the biocompatible,biodegradable polymers are copolymers of lactide (which includes d-, l-,and meso lactic acid, and d-, l-, and meso lactide) and glycolide(including glycolic acid). In another embodiment, the biocompatible,biodegradable polymer is a homopolymer of poly(dioxanone).

In one embodiment the tube is fabricated by electrostatic spinning.Electrostatic spinning uses an electrical force to transform polymersolutions into fibers. Spun fibers are exceedingly fine and are randomlyoriented in all directions. The fibers can be spun onto a mandrel suchthat the fibers are continuously added on until a tube is built up. Thediameter of the mandrel determines the internal diameter of the tube,from a practical standpoint of being able to contain sufficientmicroparticles and being easily implantable through a trocar, thediameter of the mandrel should preferably range from 1-5 mm.

The thickness of the fibers can be controlled by the concentration ofpolymer used in the solution that undergoes electrostatic spinning.However, a minimum polymer concentration is required for viable fibersand beyond a certain polymer concentration it is no longer possible tospin viable fibers. Although the range can vary with inherent viscosityof the polymer, a typical range is 1%-30% (w/v).

As mentioned above the design of the tube is such that it can be removedcomplete with its contents in the case of an adverse event. The removalis accomplished by palpating the area of implantation, finding the tubeby touch, cutting a small incision into the skin adjacent to the tubeand pulling the tube out through the incision. This requires that thetube has the mechanical properties to remain intact during this process.The inherent viscosity of the polymer used to fabricate the tube is themost critical factor to influence the mechanical properties. The rangeof the inherent viscosity to achieve adequate mechanical properties ispreferably 1.5-2.5 dl/gram.

The porosity of an electrostatically spun tube (the openings of anelectrostatically spun tube) is controlled to a large extent by thethickness of the walls of the tube and the diameter of the spun fiber.Thicker walls are prepared by having more fibers build up on the mandrelcreating greater thickness. Due to the random orientation of the fibersin the network that is formed as more fibers are added, the totalporosity of the tube decreases. Porosity is necessary since it providesa means of penetration of the surrounding physiological fluid into thetube to facilitate the diffusion of the active agent or agents from themicro-particles within. Porosity is a measure of the void spaces in amaterial, and is defined as the fraction or percentage of the totalvolume occupied by the minute open spaces. In equation form, porosity isthe volume of voids divided by the total volume expressed as a fraction,between 0-1, or as a percentage, between 0-100%. There must be limits tothe porosity since the microparticles must be contained within theinterior of the tube. Alternatively, porosity cannot be minimized to thepoint that physiological fluid is prevented from penetrating into theinterior of the tube. Ideally porosity should range from 60 to 90% andthis can be accomplished when fabricating tubes with wall thickness thatrange from 50-500 microns. For instance pores ranging between 1-20microns can be obtained with this method. Moreover, wall thicknessshould not be so excessive that it inhibits flexibility of the tube.

Alternatively, the tube can be fabricated from an extrusion processfollowed by laser drilling of holes (openings) of pre-determined size ina pre-determined pattern. As described above, the polymer that is usedto fabricate the tube is biodegradable. A preferred biodegradablepolymer is one that is soft and therefore flexible. Examples of polymersin this preferred group are poly(caprolactone) and poly(dioxanone).Here, the selection of inherent viscosity of the polymer is mostimportant. The inherent viscosity should be one that provides for thepolymer to be easily extruded and easily etched by a laser into apre-determined pattern. In polymer chemistry intrinsic viscosity isrelated to molar mass through the Mark-Houwink equation. A practicalmethod for the determination of intrinsic viscosity is with a Ubbelohdeviscometer. Inherent viscosity and intrinsic viscosity are closelyrelated. Intrinsic viscosity is defined as inherent viscosity in thelimit of infinite dilution. In a graph of inherent viscosity versussolution concentration, the y intercept (at c=0) is equal to intrinsicviscosity. As in the case of the electrostatically spun tubing the tubemust have sufficient mechanical properties that it can be pulled outfrom a small incision if there is an adverse event. The inherentviscosity of the polymer directly influences the mechanical propertiesof the tube. To meet all of these criteria the range of the inherentviscosity of the polymer should preferably range from 0.5 to 5 dl/g.

To achieve a tube-like shape the polymer is extruded from an extruderfitted with an appropriately designed die. To maintain a constantinternal diameter a stream of air can be blown into the center of thetubing. Alternatively, the tubing can be extruded along a mandrel of aspecific size. As in the case of the electrostatically spun tube, theinternal diameter can range from 1-5 mm. The minimal wall thickness ispreferably at least 25 microns; below this value the wall will not havesufficient mechanical integrity, and handling of the tube would bedifficult. The maximum wall thickness should preferably not exceed 500microns; above this value the space in the interior of the tube will belimited since the total diameter of the tube is limited by a comfortablefit in the subcutaneous space. Moreover at large wall thicknesses, theflexibility of the tube will be lowered further compromising patientcomfort, and the increase in diffusion path can decrease the diffusionrate of the active(s) from the interior of the tube. The preferred rangeof wall thickness is 50-500 microns. The outer diameter of the tubeshould preferably not exceed 5 mm; above this value the implant will betoo large to fit comfortably under the skin.

The pores (openings) are etched through the wall of the tubing using alow energy laser etching process. The precursor tube is mounted on alaser processing unit and subjected to energy from a laser beam in orderto form an implantable device having the desired geometry or patternimparted thereon. Low energy is important to prevent the heating of thepolymer that could result in the decreased reproducibility of pore shapeand diameter or even lead to a degradation of the polymer. The holes orpores have a minimum diameter of 10 microns at the outersurface of thetube, the smallest diameter pore that the laser can drill in areproducible fashion. The upper limit of the diameter can be determinedby the size of the particles. In order to prevent the loss of themajority of the micro-particles through the pores it is necessary thatthe diameter of the pore at the innersurface of the tube is less than anorder of magnitude larger than or is the same as that of the smallestdiameter micro-particles in the distribution of microparticles used inthe formulation to pack the tube. (The laser etching process may resultin pores with a diameter at the outersurface of the tube larger than thediameter at the innersurface of the tube.)

The pattern of the holes is imparted to the device by the use of a mask.A mask having the desired geometry or pattern is placed above thesubstrate and a laser beam imparts the intended pattern onto thesubstrate. The laser processing unit comprises a coordinatedmulti-motion unit that moves the laser beam in one direction and thesubstrate in another direction during the etching process. The laserbeam is projected through the mask and ablates the bioabsorbablematerial, thus imparting to the device the geometry or designcorresponding to the mask. An inert gas may be used in the laser-cuttingenvironment that minimizes or eliminates, moisture and oxygen relatedeffects during laser cutting of the material. Preferably, the laser beamis further directed through a lens before reaching the precursormaterial. The lens intensifies the beam and more precisely imparts thedesired pattern or geometry to the substrate. A beam homogenizer mayalso be used to create more uniform laser beam energy and to maintainthe laser beam energy consistency as the beam strikes the substrate.Beam energy can be controlled to reduce the laser cutting time.

The pores can also be formed by including a water-miscible semi-solid,surfactant, polymer or water soluble solid in the wall polymer. Thepores are formed when the water-miscible or soluble substance is leachedout upon contact with aqueous media. The leaching process to form thepores can be done prior to the implantation or alternatively, can occurright after implantation when physiological media contacts the surfaceof the tube. Suitable water-miscible or soluble substances includephospholipids, fatty acids, Tweens, PEG's.

Drug loaded microparticles are prepared to fill the interior of thetube. By drug-loaded microparticle is meant a particle comprising a drugphysically embedded in a polymer and having a particle size of less than1,000 microns. The microparticles can be microspheres, microcapsules, ormicrogranules. By microsphere is meant a substantially sphericalmicroparticle where the drug is uniformly dissolved or entrapped in thepolymer. By microcapsule is meant a substantially spherical particlewhere the drug is coated with a polymer. By microgranule is meant anirregularly shaped microparticle wherein the active is uniformlydissolved or entrapped in the polymer.

The particle size distribution of the microparticles preferably rangesbetween about 1 and 1,000 microns, more preferably between about 10 andabout 500 microns, and even more preferably between about 25 and about250 microns.

The size of the microparticles or particle size distribution can bemeasured or determined by techniques well-known to the skilled person,such as for example by laser diffraction or microscopy. As indicatedabove, the microparticle size is preferably linked to the size of theopenings of the tube, such that the two are coordinated to confine themicroparticles within the tube.

In order to minimize the range of the particle size distribution of themicroparticles, the microparticles can be sieved before beingincorporated into the implants of the present invention. Sieving of themicroparticles can be performed by using for example the typical meshsieves well-known to the skilled person.

Drug loaded microparticles can be prepared using any of a large numberof known processes. One preferred process, preferred because it yieldsmicroparticles with high drug loadings is the spinning disc method suchas the process described in U.S. Pat. No. 7,261,529. In order toaccommodate as much drug in the smallest space possible, minimizing theultimate size of the implant, it is highly recommended to achieveloadings of at least 10% (w/w). Drug loadings of 60-80% (w/w) arepreferred. To prepare the microparticles, the polymer is typically insolution in a suitable solvent. Suitable solvents include acetone, ethylacetate, chloroform, methylene chloride. The drug is typically insolution or suspension in the suitable solvent.

Another method to prepare the drug loaded microparticles is the emulsionmethod. To prepare microparticles using an emulsion method, the activeagent is added to an organic polymer solution either in a solid orsolution state. Rapid stirring or sonication uniformly disperses theactive agent throughout the polymer solution. The organic solution issubsequently poured into an aqueous solution containing surfactant toform polymer droplets within the aqueous phase and by stirringcontinuously the organic solvent is evaporated. The mixture is thentransferred to a large vat of water and mixing continues to extractremaining solvent and harden the droplets into microparticles. The drugloaded microparticles can be collected by filtration.

The term drug is meant to include all substances that affect somebiological response. The term drug encompasses drugs useful to anymammal including but not limited to human beings. The term drug includesbut is not limited to the following classes of drugs: therapeutic drugs,preventative drugs, and diagnostic drugs. Examples of drugs that can beincorporated into the polymer matrix are narcotic pain relievers, goldsalts, coricosteroids, hormones, anti-malarials, indole derivatives,drugs for the treatment of arthritis, anti-biotics, sulfur drugs,anti-tumor drugs, addiction-control drugs, weight control drugs, thyroidregulating drugs, analgesics, anti-hypertensive drugs, anti-inflammatoryagents, anti-tussives, anti-eleptics, anti-depressants, antiarrhythmicagents, vasodilators, antihypertensive diuretics, anti-diabetic agents,anti-coagulants, anti-tubercular agents, agents for treating psychosis,agents for the treatment of Alzheimer's disease, agents for treatingcentral nervous system disorders or syndromes, anti-HIV drugs, anti-TBagents, agents for the treatment of hepatitis, agents for the treatmentof hepatitis. The above list is not meant to be comprehensive and ismerely representative of the wide variety of drugs that may beincorporated into the microparticles.

Herein, the terms drug, active, active agent, active ingredient,compound, active compound are used interchangeable.

A preferred class of drugs are those used in the treatment or preventionof HIV, in particular in the treatment of HIV. These include proteaseinhibitors (PIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors(NRTIs and NtRTIs). Other classes are entry inhibitors including fusioninhibitors and integrase inhibitors. For HIV treatment a so-calledHighly Active Anti-Retroviral Therapy (HAART) combination is preferred.These typically comprise a backbone of two nucleoside reversetranscriptase inhibitors combined with a NNRTI or with a PI. PIs areoften combined with a so-called “booster” such as ritonavir.

One embodiment concerns an implant containing a set of microparticlescomprising the NNRTI rilpivirine (also referred to as “TMC278”), or apharmaceutically acceptable salt thereof, such as the hydrochloric acidsalt. Preferred is rilpivirine (=free base).

One embodiment concerns an implant wherein one set of microparticlescontains a NRTI and another set of microparticles contains an NNRTI.

One embodiment concerns an implant wherein one set of microparticlescontains a NNRTI and another set of microparticles contains a PI.

Another preferred class of drugs is those that are used in the treatmentof hepatitis C. These include ribavirin, interferon, HCV (Hepatitis CVirus) protease inhibitors, HCV polymerase inhibitors. Also here,combinations are preferred.

One embodiment concerns an implant wherein the microparticles contain atleast one drug selected from an HIV inhibitor or an HCV inhibitor.

The polymer used to fabricate the microparticles is a biocompatible,biodegradable polymer. Suitable biocompatible, biodegradable polymerscomprise aliphatic polyesters, poly(amino acids), copoly(ether-esters),polyalkylene oxalates, polyamides, poly(iminocarbonates),poly(orthoesters), polyoxaesters, polyamidoesters, polyoxaesterscontaining amine groups, poly(anhydrides), polyphosphazenes, and blendsthereof. For the purpose of this invention aliphatic polyesters includebut are not limited to homopolymers and copolymers of lactide (whichincludes d-, l-, and meso lactic acid, and d-, l-, and meso lactide),glycolide (including glycolic acid), epsilon-caprolactone, p-dioxanone(1,4-dioxan-2-one), and trimethylene carbonate (1,3-dioxan-2-one). Inone embodiment, the biocompatible, biodegradable polymers are copolymersof lactide (which includes d-, l-, and meso lactic acid, and d-, l-, andmeso lactide) and glycolide (including glycolic acid). In anotherembodiment, the biocompatible, biodegradable polymer is a co-polymer oflactide and glycolide with a mole percent of lactide that ranges from85% to 50%.

In one embodiment of the present invention the microparticles contain inaddition to the polymer and the one or more drugs, a surfactant.Surfactants are utilized to improve the wetability of hydrophobiccomponents and they are typically ampiphilic molecules that contain bothhydrophilic and lipophilic groups. The hydrophile-lipophile balance(HLB) number is used as a measure of the ratio of these groups. It is avalue between 0-60 defining the affinity of a surfactant for water oroil. HLB numbers are calculated for nonionic surfactants using themolecular weights of the hydrophilic and hydrophobic portions of themolecule, and these surfactants have numbers ranging from 0-20. The HLBvalues that are associated with ionic surfactants are not calculated butrather they are given a value based on its relative or comparisonsurfactant behavior.

Surfactants with HLB numbers >10 have an affinity for water(hydrophilic) and surfactants with HLB number <10 have an affinity foroil (lipophilic).

Surfactants include non-ionic surfactants and ionic surfactants. Theionic surfactants include cationic, anionic and zwitterionic surfactantssuch as the fatty acid salts e.g. sodium oleate, sodium lauryl sulfate,sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodiummyristate, sodium palmitate, sodium state, sodium ricinoleate and thelike; such as bile salts e.g. sodium cholate, sodium taurocholate,sodium glycocholate and the like; such as phospholipids e.g. egg/soylecithin, hydroxylated lecithin, lysophosphatidylcholine,phosphatidylcholine, phosphatidyl ethanolamine, phosphatidyl glycerol,phosphatidyl serine and the like; such as phosphoric acid esters e.g.diethanolammonium polyoxyethylene-10 oleyl ether phosphate,esterification products of fatty alcohols or fatty alcohol ethoxylateswith phosphoric acid or anhydride; such as carboxylates e.g.succinylated monoglycerides, sodium stearyl fumarate, stearoyl propyleneglycol hydrogen succinate, mono/diacetylated tartaric acid esters ofmono- and diglycerides, citric acid esters of mono- and diglycerides,glyceryl-lacto esters of fatty acids, lactylic esters of fatty acids,calcium/sodium stearoyl-2-lactylate, calcium/sodium stearoyl lactylate,alginate salts, propylene glycol alginate, ether carboxylates and thelike; such as sulfates and sulfonates e.g. ethoxylated alkyl sulfates,alkyl benzene sulfates, alpha-olefin sulfonates, acyl isethionates, acyltaurates, alkyl glyceryl ether sulfonates, octyl sulfosuccinatedisodium, disodium undecyleneamido-MEA-sulfosuccinate and the like; suchas cationic surfactants e.g. hexadecyl triammonium bromide, decyltrimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecylammonium chloride, alkyl benzyldimethylammonium salts, diisobutylphenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts,betaines (lauryl betaine), ethoxylated amines (polyoxyethylene-15coconut amine) and the like.

Preferred surfactants in the present invention are non-ionicsurfactants.

Suitable non-ionic surfactants which may be used in the presentinvention comprise:

a) Polyethylene glycol fatty acid monoesters comprising esters of lauricacid, oleic acid, stearic acid, ricinoic acid and the like with PEG 6,7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400,600 and the like, for instance PEG-6 laurate or stearate, PEG-7 oleateor laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate orstearate, PEG-10 laurate or oleate or stearate, PEG-12 laurate or oleateor stearate or ricinoleate, PEG-15 stearate or oleate, PEG-20 laurate oroleate or stearate, PEG-25 stearate, PEG-32 laurate or oleate orstearate, PEG-30 stearate, PEG-40 laurate or oleate or stearate, PEG-45stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or stearate,PEG-200 oleate, PEG-400 oleate, PEG-600 oleate; (the surfactantsbelonging to this group are for instance known as Cithrol, Algon,Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet,Albunol, Lactomul)

b) Polyethylene glycol fatty acid diesters comprising diesters of lauricacid, stearic acid, palmic acid, oleic acid and the like with PEG-8, 10,12, 20, 32, 400 and the like, for instance PEG-8 dilaurate ordistearate, PEG-10 dipalmitate, PEG-12 dilaurate or distearate ordioleate, PEG-20 dilaurate or distearate or dioleate PEG-32 dilaurate ordistearate or dioleate, PEG-400 dioleate or distearate; (the surfactantsbelonging to this group are for instance known as Mapeg, Polyalso,Kessco, Cithrol)

c) Polyethylene glycol fatty acid mono- and diester mixtures such as forexample PEG 4-150 mono and dilaurate, PEG 4-150 mono and dioleate, PEG4-150 mono and distearate and the like; (the surfactants belonging tothis group are for instance known as Kessco)

d) Polyethylene glycol glycerol fatty acid esters such as for instancePEG-20 glyceryl laurate or glyceryl stearate or glyceryl oleate, PEG-30glyceryl laurate or glyceryl oleate, PEG-15 glyceryl laurate, PEG-40glyceryl laurate and the like; (the surfactants belonging to this groupare for instance known as Tagat, Glycerox L, Capmul),

e) Alcohol-oil transesterification products comprising esters ofalcohols or polyalcohols such as glycerol, propylene glycol, ethyleneglycol, polyethylene glycol, sorbitol, pentaerythritol and the like withnatural and/or hydrogenated oils or oil-soluble vitamins such as castoroil, hydrogenated castor oil, vitamin A, vitamin D, vitamin E, vitaminK, an edible vegetable oil e.g. corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, almond oil and the like, such as PEG-20castor oil or hydrogenated castor oil or corn glycerides or almondglycerides, PEG-23 castor oil, PEG-25 hydrogenated castor oil ortrioleate, PEG-35 castor oil, PEG-30 castor oil or hydrogenated castoroil, PEG-38 castor oil, PEG-40 castor oil or hydrogenated castor oil orpalm kernel oil, PEG-45 hydrogenated castor oil, PEG-50 castor oil orhydrogenated castor oil, PEG-56 castor oil, PEG-60 castor oil orhydrogenated castor oil or corn glycerides or almond glycerides, PEG-80hydrogenated castor oil, PEG-100 castor oil or hydrogenated castor oil,PEG-200 castor oil, PEG-8 caprylic/capric glycerides, PEG-6caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoylmacrogol glyceride, tocopheryl PEG-1000 succinate (TPGS); (thesurfactants belonging to this group are for instance known as Emalex,Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex,Crovol, Labrasol, Softigen, Gelucire, Vitamin E TPGS),

f) polyglycerized fatty acids comprising polyglycerol esters of fattyacids such as for instance polyglyceryl-10 laurate or oleate orstearate, polyglyceryl-10 mono and dioleate, polyglycerylpolyricinoleate and the like; (the surfactants belonging to this groupare for instance known as Nikkol Decaglyn, Caprol or Polymuls)

g) Sterol derivatives comprising polyethylene glycol derivatives ofsterol such as PEG-24 cholesterol ether, PEG-30 cholestanol, PEG-25phyto sterol, PEG-30 soya sterol and the like; (the surfactantsbelonging to this group are for instance known as Solulan™ or NikkolBPSH)

h) Polyethylene glycol sorbitan fatty acid esters such as for examplePEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate or sorbitantristearate or sorbitan monooleate or sorbitan trioleate or sorbitanmonoisostearate or sorbitan monopalmiate or sorbitan monostearate, PEG-4sorbitan monolaurate, PEG-5 sorbitan monooleate, PEG-6 sorbitanmonooleate or sorbitan monolaurate or sorbitan monostearate, PEG-8sorbitan monostearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitanoleate or sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-80sorbitan monolaurate, PEG sorbitol hexaoleate (Atlas G-1086) and thelike; (the surfactants belonging to this group are for instance known asLiposorb, Tween, Dacol MSS, Nikkol, Emalex, Atlas)

i) Polyethylene glycol alkyl ethers such as for instance PEG-10 oleylether or cetyl ether or stearyl ether, PEG-20 oleyl ether or cetyl etheror stearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether (laureth-23),PEG-100 stearyl ether and the like; (the surfactants belonging to thisgroup are for instance known as Volpo, Brij)

j) Sugar esters such as for instance sucrose distearate/monostearate,sucrose monostearate or monopalmitate or monolaurate and the like; (thesurfactants belonging to this group are for instance known as Sucroester, Crodesta, Saccharose monolaurate)

k) Polyethylene glycol alkyl phenols such as for instance PEG-10-100nonyl phenol (Triton X series), PEG-15-100 ocyl phenol ether (Triton Nseries) and the like;

l) Polyoxyethylene-polyoxypropylene block copolymers (poloxamers) suchas for instance poloxamer 108, poloxamer 188, poloxamer 237, poloxamer288 and the like; (the surfactants belonging to this group are forinstance known as Synperonic PE, Pluronic, Emkalyx, Lutrol™, Supronic,Monolan, Pluracare, Plurodac)

More preferred surfactants are non-ionic surfactants with HLB values of20 or less. A suitable surfactant is F108 (BASF).

To facilitate the loading of the microparticles into the tubes ahydrogel can be used as a binder to bind together the different sets ofmicroparticles prior to the loading of the micro-particles into thetubes. Binders can be carefully selected to not only bind but to serveas a means to wick moisture into the interior of the tube facilitatingdrug diffusion particularly when microparticles are composed ofhydrophobic drugs. Moreover, the binder can be chosen to actuallyenhance the solubility of poorly water soluble compounds formulated intothe microparticles. This can be accomplished by for instance providing alow pH environment for those compounds that are more soluble at low pH.Alternatively, the binder can be a polymer that self-emulsifies in ahydrated system providing a surfactant environment for poorlywater-soluble drugs incorporated into the microparticles. Some examplesof binders include albumin, casein, waxes, starch, crosslinked starch,simple sugars, glucose, polysucrose, polyvinyl alcohol, gelatine,modified celluloses, carboxymethylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropyl-ethylcellulose, hydroxypropyl-methyl cellulose, sodiumcarboxymethyl cellulose, cellulose acetate, sodium alginate, hyaluronicacid, hyaluronic acid derivatives, polyvinyl pyrrolidone, polymaleicanhydride esters, polyortho esters, polyethyleneamine, glycols,polyethylene glycol, methoxypolyethylene glycol, ethoxypolyethyleneglycol, polyethylene oxide, poly(1,3bis(p-carboxyphenoxy)propane-co-sebacic anhydride,N,N-diethylaminoacetate, block copolymers of polyoxyethylene andpolyoxypropylene, polyacrylic acid and polyacrylic acid derivatives,guar gum, carob ban gum, chitins, self emulsifying polymers or agents.An effective amount of binder is one with sufficient viscosity to bindthe particles but with a low solids content in order to minimize theamount of space it requires in the interior of the tube.

In one embodiment of the present invention the hydrogel itself containsone or more drugs in addition to the one or more drugs present in themicroparticles. This facilitates in obtaining high initial plasmaconcentrations of the one or more drugs.

The microparticles or microparticle/hydrogel mixture can be introducedin the tubes by manual techniques or by automatic techniques. Manualtechniques include the transfer of mixture by spatula into the tube.Automatic techniques include the use of conventional filling machinesused in the pharmaceutical industry.

To close the tube to completely surround the cavity, the ends of thetubes can be heat sealed. This can be accomplished for instance by usinga Bovie low temperature surgical cautery. Prior to applying heat, asmall piece of tubing material is first inserted into the end section ofthe tubing being sealed and then heat is applied to the local end areato make the material melt; the end can then be squeezed by hand to forma seal. One end of the tube is first sealed and then the tubing isfilled with the designated content. After that, the open end can besealed in the same way. There are many other possible ways to seal theends. For example, a regular heat sealer can be used where the endsection of the tubing to be sealed is placed in between the two lips ofthe sealer. Sealing is accomplished by applying heat and pressure at thesame time.

The ends may also be glue sealed by using a suitable adhesive; smallamount of the adhesive can be placed inside the tubing in the tip areaand then pressure is applied to compress the tip of the end. Typically apre-determined holding time is necessary to form a solid seal.

The implant may have any shape including but not limited to a disc,sphere or cylinder but preferably the implant is a cylinder. The size ofthe cylinder can be between 1 and 5 mm in diameter and 0.5 and 5 cm inlength, more preferably between 1 and 4 mm in diameter and 1 and 5 cm inlength. It is particularly useful in anti-virus therapy such as anti-HIVtherapy and anti-hepatitis therapy.

EXAMPLES Example 1

A binder solution was prepared using poly(acrylic acid) (PAA) (Aldrich)of molecular weight 1.25 million kilodaltons. Three hydrogel solutionconcentrations were prepared using deionized water to dissolve thepoly(acrylic acid). The concentrations were 5% (w/w), 0.5% (w/w), 0.25%(w/w). Although mixtures of microparticles were obtained with all 3hydrogels, the mixture easiest to work with in terms of not being tooviscous to make dispersion of microparticle in the hydrogel difficultand in terms of the hydrogel not being too runny for easy loading intothe tube was the 0.5% (w/w). The pH of each hydrogel was measured usingpH paper, the pH of the 5% hydrogel was between 2-3, the other twohydrogels measured 3.

The particle/hydrogel mixture can be prepared such that it is one parthydrogel and 2 parts microparticles and in this way minimizing the spacein the tube that is required by the gel and maximizing the internalspace for the microparticles. Microparticles composed of 70% (w/w)TMC278 and 30% (w/w) poly(lactic co-glycolic acid) (PLGA) (DLG 5050 1ASurmodics Pharmaceuticals, Birmingham, Ala.) were prepared using thespinning disc method. In general, to prepare particles using thespinning disc method, a disc of specific size is selected and mounted ona motor with a tunable rotation rate to control disc speed. The polymeris dissolved in a suitable solvent, such as for example acetone, and thedrug is added to the polymer solution and stirred. The resulting mixtureis fed to the disc at a specific rate. As the disc spins, centripetalforce forms droplets or particles to the outer edge of the disc. Theparticles are directed to a drying cone that is pre-set with a gradientof temperatures. The solvent is removed from the particles in thisdrying step causing the particles to harden or solidify and theparticles are collected.

In this example, a 4% (w/v) PLGA solution was prepared in acetone. Thedisc (Southwest Research Institute, San Antonio, Tex.) speed was 9250rpm, the disc size was 7.62 cm, the feed rate was 45 g/min, cone outlettemperature ranged from 45-48° C. The TMC278 was added into the PLGAsolution and stirred for approximately 15-20 minutes before being fedinto the disc. The particle size distribution was measured using aMalvern Mastersizer (Malvern Instruments, Ltd, Worcestershire, UK.Results: the d₁₀ was 29 microns, the d₅₀ was 48 microns and the d₉₀ was69 microns.

The tubes were prepared by electrostatic spinning of a 120 mg/mlpoly(dioxanone) in hexafluoroisopropanol. The inner diameter of the tubewas 3 mm and the wall thickness was 500 microns. The length of the tubeused was 2.54 cm. Scanning electron microscopy (JEOL JSM 5900LV, Tokyo,Japan) analysis of the tubes indicated that the openings (pores) in thenetwork formed by the randomly oriented fibers were in the range of 1-20microns. Initially, one end of the tubes was heat sealed. Heat sealingwas accomplished using a Bovie low temperature surgical cautery. Priorto applying heat, a small piece of the tubing material was firstinserted into the end section of the tubing being sealed and then heatwas applied to the local end area to make the material melt; the end wasthen squeezed by hand to form a seal. After the one end was sealed, thetube was weighted together with a small piece of tubing material thatwill be added to the other end of the tube when this end will be heatsealed (mass of the empty tube was noted) and subsequently filled withthe microparticle/hydrogel mixture using a spatula. The filling wasfollowed by heat sealing of the second end of the tube using the sameprocedure as outlined above (with the addition of the small piece). Thesealed tube was weighed. The difference in weight between the filled andunfilled tube is equal to mass of the contents. Details of the contentsof each tube are summarized in Table 1.

TABLE 1 Electrostatically spun tubes with microparticle/PAA mixture Massof contents in Mass of Concen- tube (mg) TMC278 tration of pH(microparticle/ in Sample ID gel (w/w) of gel hydrogel mixture) tube(mg) 3895-42-1 5% 2-3 45.12 16 3895-42-2 0.5  3 59.83 21 3895-42-3 0.253 36.1  17

The samples were placed in a Method I sampling system using a HansonDissolution Tester (Hanson Research Corp., Chatsworth, Calif.) using 500ml elution vessels. The media was 500 ml distilled water and sampleswere taken at 1, 3, 7, 10, and 14 days. The release data are summarizedin Table 2. Experiments were performed at 37° C.

TABLE 2 TMC278 elution from poly(acrylic acid) gels in electrospun tubes3895-42-1 3895-42-2 3895-42-3 micrograms micrograms micrograms Timeeluted/ eluted/ eluted/ (Day) % of total load % of total load % of totalload  1 434/2.7 444/2.1 429/2.5  3 445/2.8 398/1.9 408/2.4  7 443/2.8388/1.8 400/2.3 10 443/2.8 402/1.9 381/2.2 14 448/2.8 399/1.9 406/2.4

The solubility of TMC278 dramatically increases at pH=2. Solubilityexperiments demonstrate that the solubility in water is 950 timesgreater at pH of 2 relative to pH of 7. The use of an acidic binder gelthat can effectively lower pH, can increase the rate of elution ofTMC278 from the polymer matrix. Increasing the concentration of theacidic polymer in the gel can depress the pH even further (Table 1). Asillustrated in Table 2, dispersing the TMC278 microparticles in a 5%(w/w) poly(acrylic acid) gel where the pH is between 2 and 3, results ina larger amount of TMC278 eluting from the microparticles relative toTMC278 microparticles dispersed in the less concentrated hydrogels,where the pH is 3.

Example 2

A 3% (w/v) of carboxymethylcellulose (CMC; Hercules, 7H3SFPH) gel wasprepared in PBS. When prepared in water the viscosity of the gel wouldbe 3000-6000 cps. However the viscosity of the polymer drops by ⅔ whenprepared in a salt solution due to its sensitivity to ionic strength andtherefore does readily mix with the microparticles. Microparticlescomposed of 70% (w/w) TMC278 and 30% (w/w) poly(lactic co-glycolic acid)(PLGA) (DLG 5050 1A, Surmodics Pharmaceuticals, Birmingham, Ala.) wereprepared using the spinning disc method. In short, a 4% (w/v) polymersolution was prepared in acetone. The disc speed and size were 9250 rpmand 7.62 cm, respectively. The feed rate was 45 g/min and the coneoutlet temperature ranged from 45-48° C. The TMC278 was added into thePLGA solution and stirred for approximately 15-20 minutes before beingfed into the disc. The particle size distribution was measured using aMalvern Mastersizer (Malvern Instruments, Worcestshire, UK). Resultsindicated the d₁₀ at 29 microns, the d₅₀ at 48 microns and the d₉₀ at 69microns. A 2 mg sample of the microparticles was mixed with 2 ml of the3% CMC gel. The total loading of TMC278 in this mixture was 2.25% (w/w).

Poly(lactic co-glycolic acid) with a molar ratio of 85/15 oflactide/glycolide was used to prepare the tubing. The tubing wasextruded using a small scale, commercial extrusion line comprised of a1″ single screw extruder (Davis Standard), a water cooling trough, apuller and a cutter. An in-line laser diameter measuring system was alsoused to monitor the diameter and the roundness of the tubing. In theextrusion process, the raw material in resin form was fed from a topmounted hopper into the barrel of the extruder where the rotating screwforced the resin forward into the barrel which was heated to the desiredmelt temperature. In the three heating zones of the extruder a suitabletemperature profile was set and maintained. This allowed the plasticresin to melt gradually as it was pushed through the barrel (lower riskof overheating which may cause degradation of the polymer).

At the front end of the barrel, the molten plastic left the screw andtraveled through a screen pack to remove any contaminants in the meltwhich also helped to establish a more stable back pressure. Afterpassing through the breaker plate molten plastic entered the die. Thedie was tubular with a mandrel in the center to create an annularstructure for the creation of tubular profile. Small amount of air wasinjected inside of the polymer tubing through the tip of the mandrel(air flow rate controlled by an air flow controller). The extrudate inthe form of tubing was pulled by a downstream rubber roller through acooling water trough where the tubing was cooled and solidified.Downstream to the puller was a cuter where the extruded tubing with thefinal size was cut to pre-determined length and collected. An in-linelaser diameter measuring system was installed after the cooling troughand before the puller for continuous in-line measuring and monitoring ofthe extruded tubing dimensions.

The extruded tube was perforated with 10 micron holes using a laser. Apattern of 20 rows×20 columns of holes was used to perforate the polymertubing. The interior diameter of the tube was 1.5 mm and the outerdiameter was 1.6 mm. A 2.54 cm sample was cut from the tubing and heatsealed on one end (according to the same procedure as described inexample 1). A 33.67 mg sample of the microparticle/CMC gel mixture wastransferred into the perforated tube by using a spatula and the secondend of the tube was heat sealed as described above.

The sample was placed in a Method I sampling system in a HansonDissolution Tester (Chatsworth, Calif.) using 500 ml vessels. The mediawas 500 ml distilled water. Samples were taken at 1, 3, 7, 10, and 14days. The release data is summarized in

Table 3. Experiments were performed at 37° C.

TABLE 3 TMC278 release from microparticle in a perforated tubeCumulative amount Cumulative Release of TMC278 of TMC278; Day(micrograms) released (Percent of Total load)  1  58 7.6   3  59 7.8   7112 14.7 10 125 16.4 14 138 18.2

Example 3

A 0.5% (w/w) poly(acrylic acid) (Aldrich) gel was prepared in water and400 mg of the gel was mixed with 960 mg of TMC278 particles.Microparticles were composed of 70% (w/w) of TMC278 and 30% (w/w)poly(lactic co-glycolic acid) (DLG 5050 1A, Surmodics Pharmaceuticals,Birmingham, Ala.) and prepared according to the procedure described inExample 1 and 2). The particle size distribution of the microparticleswas measured as described above; d₁₀ was 29, d₅₀=48 and d₉₀ was 68microns. The mixture was packed into a poly(dioxanone) tube which wasprepared according to the procedure described in Example 2. The tube wasperforated using laser technology as described above. The tube was 30 mmlong, 5 mm sections from each edge were unperforated. The perforationsin the 30 mm length in the middle section were arranged in 40 rows ofholes and 2400 holes per row. The diameter of each hole was 50 microns.The mass of the tube before filling was 102.01 mg. The mass of the tubeafter filling was 190.64 mg (the calculated concentration of TMC278 inthe tube is 43.4 mg).

Two more samples were prepared in this fashion, and the mass of themicroparticle/gel mixture in the tube was 53.7 mg and 46.3 mg,respectively. HPLC analysis confirmed the content of 39.2 and 32.1 mg ofTMC278 in the respective tubes.

Example 4

Electrostatically spun poly(dioxanone) tubes were prepared using a 120mg/ml polymer solution in hexafluoroisopropanol. The wall thickness ofthe tube was 500 microns. A microparticle mixture was prepared usingmicroparticles with a particle size distribution of d₁₀=29, d₅₀=48 andd₉₀=68 microns. The composition of the microparticles was 70% (w/w)TMC278 and 30% (w/w) PLGA 50/50 (0.1 dl/g). A sample of 1200 mg ofmicroparticles was mixed with 500 mg of a 0.5% poly(acrylic acid)aqueous gel. The mass of the 2 cm long tube before filling was 82.8 mgand 203.0 mg after filling.

Example 5

The microparticle mixture described in Example 4 was used to fill anelectrostatically spun tube that was prepared from a 150 mg/mlpolydioxanone solution, as prepared in Example 1. The wall thickness ofthe tube was 200 microns. The mass of the 2 cm tube before filling was29.0 mg and after filling was 129.3 mg.

Example 6

The microparticle mixture described in Example 4 was used to fill anelectrostatically spun tube that was prepared from a 60 mg/mlpolydioxanone solution, as prepared in Example 1. The wall thickness ofthe tube was 500 microns. The mass of the 2 cm tube before filling was55.4 mg and after filling was 151.9 mg.

Example 7

Two different sets of microparticles containing TMC278 were prepared.One set of microparticles was prepared using 4% (w/v) poly(lacticco-glycolic acid) (DLG 5050 2A, Surmodics Pharmaceuticals, Birmingham,Ala.) acetone solution. The micro-particles were prepared using spinningdisc method as described in Example 1. The disc speed was 7500 rpm andthe disc size was 7.62 cm. The feed rate was 45 g/min and the coneoutlet temperature was 45-48° C. The majority of the particles formedwere in the range of 50-75 microns, and the loading of TMC278 in theparticles was 70% (w/w). The second set of microparticles were preparedfrom 4% (w/v) poly(lactic co-glycolic acid) (DLG 5050 1A, containing2.5% (w/w) oligomers of lactide-glycolide (5050 DLG 1CA, SurmodicsPharmaceutics, Birmingham, Ala.) in acetone solution. TMC278 loading inthe second set of microparticles was also 70% w/w. These were alsoprepared using a spinning disc method. The disc speed was 9250 rpm, thefeed rate was 50-55 g/min, and the cone outlet temp was 45° C. A sampleof 519 mg of 0.5% poly(acrylic acid) aqueous gel was mixed with 606 mgof the TMC278 microparticles prepared from the DLG 5050 2A polymer and599 mg of TMC278 particles prepared with the DLG 5050 1A with added DLG1CA. A poly(dioxanone) perforated tube as described in Example 3 wasfilled with the microparticle mixture. The mass of the empty tube was85.01 mg and the mass of the tube filled with the microparticle mixturewas 211 mg.

Example 8

Two different sets of microparticles were prepared, one set containedTMC278, a potent non-nucleoside reverse transcriptase inhibitor for thetreatment of HIV. The second set contained TMC114, a protease inhibitorfor the treatment of HIV, also known as darunavir. The TMC278microparticles were prepared using the spinning disc method as describedabove. For these particles, a 4% (w/v) poly(lactide co-glycolide) (5050DLG 1A, Surmodics Pharmaceuticals, Birmingham, Ala.) acetone solutionwith added 7.5% (w/v) oligomeric poly(lactide co-glycolide) (5050 DLG1CA, Surmodics Pharmaceutical, Birmingham, Ala.) was prepared. Theloading of TMC278 relative to the polymer was 70% (w/w). Particles sizesranged from 20-75 microns.

The second set of microparticles was prepared by dissolving TMC114 intoa 4% (w/v) poly(lactide co-glycolide) (5050 DLG 1A, SurmodicsPharmaceuticals, Birmingham, Ala.) acetone solution. The drug-polymersolution was fed onto a 7.62 cm disc that was spinning at 9500 rpm at afeed rate of 45 g/min. The disc chamber outlet temperature (cone outlettemperature) was 42-45° C., and the loading of TMC114 in themicroparticles was 70% (w/w). A mixture of the microparticles wasprepared by preparing a 0.5% (w/w) poly(acrylic acid) aqueous gel andmixing 507 mg of the gel with 502 mg of the TMC78 microparticles and 507mg of the TMC114 microparticles. Microparticle mixture was packed into apoly(dioxanone) extruded and perforated tube (see Example 3). Pattern ofperforations and size of perforations are described in Example 3. Asnoted earlier, the tube was initially heat-sealed on one end, filledwith mixture, and heat-sealed on the other end. Five different sampleswere prepared and elution rate of the two drugs was measured (Table 4).The media used to measure elution rate was 90% (v/v) methanol and 10%(v/v) water due to the extreme insolubility of TMC278 in water.

TABLE 4 Cumulative release of TMC114 and TMC278 from microparticlessequestered in poly(dioxanone) extruded and perforated tubes Mass ofmicroparticle/ TMC114 TMC114 TMC114 TMC278 TMC278 TMC278 gel mixture 1day 3 days 7 day 1 day 3 day 7 day Sample # (mg) (mg) (mg) (mg) (mg)(mg) (mg) 3998- 62.93 3.0 16 22 7.1 13.1 21.4 8-1 3998- 80.71 3.5 20 338.5 15.7 35.5 8-2 3998- 72.88 4.0 19 19 8.4 16.5 19.5 8-3 3998- 74.964.0 22 28 9.8 16.8 25.4 8-4 3998- 66.77 3.8 22 22 9.3 14.8 19.7 8-58-5

Example 9

In Vivo Testing of Electrostatically Spun Tube Containing Two Sets ofMicroparticles

Tubes were electrostatically spun from a 100 mg/ml polydioxanone(IV_(HFIP)=1.99 dl/g) hexafluoroisopropanol solution. A 4 mm mandrel wasused to provide a consistent inner diameter of 4 mm. The rotationalspeed of the mandrel was 400 rpm, the charging voltage range was 20/−10kV, and the pump flow rate was 10 ml/hour. The resulting wall thicknesswas 500 microns. Fiber diameters were 1-2 microns and the average poresize formed from the network of fibers was 20 microns as determined byScanning Electron Microscopy.

The microparticles were prepared by the spinning disc method using apolymer/acetone solution with a concentration ranging from 3-4% (w/w).Two sets of microparticles were prepared. The target composition of oneset was 70% (w/w) TMC278 and 30% (w/w) PLGA 50/50 (LakeshoreBiomaterials IV_(HFIP)=0.79 dl/g). The target composition of the otherset of microparticles was 70% (w/w) of compound 1 (=compound 14 ofWO01/25240) and 30% (w/w) PLGA 50/50 (Lakeshore BiomaterialsIV_(HFIP)=0.18 dl/g). This compound 1 has the following structure andwill be referred to hereinafter as compound 1:

The disc speed ranged from 7300-7500 rpm, cone inlet and outlettemperatures were 56-57° C. and 33.5° C., respectively. The loading ofTMC278 and compound 1 in the respective microparticles was measured byHPLC, and TMC278 and compound 1 concentrations were 65% (w/w) and 35%(w/w) respectively. The difference between the target and actualconcentration for compound 1 illustrates the greater difficulty inencapsulation of compound 1.

The microparticle size range was determined by placing a randomlyselected sample on the stage of an optical microscope and using a rulerto measure the various sizes of the microparticles in the randomlyselected sample. The resulting size range of the TMC278 microparticleswas 10-100 micron, and that of the compound 1 microparticles was 20-100microns.

Mixing of the two types of microparticles was accomplished bytransferring both sets of microparticles into a 50 mL glass roundbottomflask and mixing with an overhead mixer fitted with a glass stirring rodand teflon paddle. The microparticles were dry-mixed at 100 rpm for 30minutes (previously determined to be a sufficient mixing time to achievea homogeneous reproducible mixture of both microparticles).

Approximately 133 mg of the microparticle mixture was introduced intothe electrostatically prepared tubes using a spatula.

The prepared tubes were implanted into the subcutaneous space on theback of four male Sprague-Dawley rats weighing between 250-350 grams.The dose of TMC278 was 139 mg/kg and the dose of compound 1 was 64mg/kg. The tail vein was sampled at pre-determined time points. Bloodsamples were immediately centrifuged to extract the plasma, plasma wasanalyzed for compound 1 and TMC278 by LC/MS/MS. The lower limit ofquantitation was 0.4 ng/ml and 2 ng/ml for TMC278 and compound 1,respectively. Values for the tested plasma concentrations at each timepoint for each drug are tabulated in Table 5.

TABLE 5 TMC278 and compound 1 plasma concentrations 3 hour 1 day 3 day 7day 14 day 28 day 35 day Drug Animal # ng/ml ng/ml ng/ml ng/ml ng/mlng/ml ng/ml TMC278 1 0.505 <0.4 <0.4 0.421 <0.4 <0.4 <0.4 TMC278 2 0.5620.441 0.518 0.645 <0.4 <0.4 0.527 TMC278 3 0.462 <0.4 <0.4 <0.4 <0.4<0.4 0.769 TMC278 4 0.576 0.575 0.549 <0.4 0.424 0.475 0.400 compound 11 3.93 6.39 10.0 9.95 7.17 6.07 5.75 compound 1 2 2.37 12.6 15.1 13.612.7 8.86 12.0 compound 1 3 4.08 9.95 14.2 13.2 16.6 12.4 20.0 compound1 4 4.46 10.5 15.9 13.0 9.89 10.5 11.6

Example 10

In Vivo Testing of Laser Drilled Melt Extruded Tube Containing Two Setsof Microparticles

Tubes with inner diameter of 4.5 mm were extruded from polydioxanone(IV_(HFIP)=1.99 dl/g) using a ¾ inch single screw extruder fitted with atube die. The dimensions of the tube were monitored using an in-linelaser diameter measuring system and maintained using a puller. Followingthe extrusion the tubes were laser drilled. In preparation for the laserdrilling a mask design was prepared that located the holes 260 micronsapart from one another. Scanning electron microscopy was used to sizethe inner and outer diameter of the holes. Results showed that the outerdiameter was averaged 100 microns and that of the inner averaged 30microns. The microparticles were prepared as described in Example 9.Approximately 133 mg of the microparticle mixture was introduced intothe tubes.

The prepared tubes were implanted into the subcutaneous space on theback of four male Sprague-Dawley rats weighing between 250-350 grams.The dose of TMC278 was 139 mg/kg and the dose of compound 1 was 64mg/kg. The tail vein was sampled at pre-determined time points. Bloodsamples were immediately centrifuged to extract the plasma, and plasmawas analyzed for compound 1 and TMC278 by LC/MS/MS. The lower limit ofquantitation for TMC278 and compound 1 was 0.4 ng/ml and 2.0 ng/ml,respectively. Values for the tested plasma concentrations at each timepoint for each drug are tabulated in Table 6.

TABLE 6 TMC278 and compound 1 plasma concentrations Animal 3 hour 1 day3 day 7 day 14 day 28 day 35 day Analyte # ng/ml ng/ml ng/ml ng/ml ng/mlng/ml ng/ml TMC278 1 0.551 <0.4 <0.4 <0.4 <0.4 <0.4 <0.4 TMC278 2 1.420.432 <0.4 0.4 <0.4 0.451 0.403 TMC278 3 2.51 1.22 1.14 0.695 0.425 1.362.11 TMC278 4 1.61 <0.4 <0.4 <0.4 0.456 0.773 0.881 compound 1 1 2.88 <2<2 <2 <2 <2 <2 compound 1 2 16.4 4.20 3.35 3.44 2.70 4.32 3.56 compound1 3 27.0 9.25 6.06 3.13 2.26 13.0 13.0 compound 1 4 16.5 3.71 <2 <2 3.664.30 2.57

Example 11

In Vivo Testing of Laser Drilled Melt Extruded Tube Containing Two Setsof Microparticles Formulated with F108

The laser drilled melt extruded tube was prepared as described above inexample 10. The microparticles were prepared by the spinning disc methodusing a 3% (w/w) polymer/acetone solution. Two sets of microparticleswere prepared. The target composition of one set was 70% (w/w) TMC278,20% (w/w) PLGA 50/50 (Lakeshore Biomaterials IV_(HFIP)=0.79 dl/g), and10% (w/w) F108 (BASF). The target composition of the other set ofmicroparticles was 70% (w/w) compound 1, 20% (w/w) PLGA 50/50 (LakeshoreBiomaterials IV_(HFIP)=0.18 dl/g), and 10% (w/w) F108. The F108 wasadded to the polymer solution.

The conditions of disc speed and cone inlet and outlet temperatures werethe same as those used in examples 9 and 10. The loadings of TMC278 andcompound 1 in the microparticles was measured by HPLC, resultingconcentrations were 61% (w/w) and 50% (w/w) respectively.

The size range of the microparticles was determined by randomlyselecting a sample of microparticles and placing them on the stage of anoptical microscope and using a ruler to measure the various sizes of themicroparticles in the randomly selected sample. The size range of theTMC278 and compound 1 microparticles was 10-100 microns and 20-100microns, respectively. Microparticles were mixed as described in example9. Approximately 133 mg of the microparticle mixture was introduced intotubes using a spatula to transfer the contents.

The prepared tubes were implanted into the subcutaneous space on theback of four male Sprague-Dawley rats weighing between 250-350 grams.The dose of TMC278 and compound 1 was 109 mg/kg and 78 mg/kg,respectively. The tail vein was sampled at pre-determined time points.Blood samples were immediately centrifuged to extract the plasma, plasmawas analyzed for compound 1 and TMC278 by LC/MS/MS. The lower limit ofquantitation for TMC278 and compound 1 was 0.4 ng/ml and 2 ng/ml,respectively. The results of the tested plasma concentrations for eachtime point for each drug are tabulated in Table 7.

TABLE 7 TMC278 and compound 1 plasma concentrations Animal 3 hour 1 day3 day 7 day 14 day 28 day 35 day Drug # ng/ml ng/ml ng/ml ng/ml ng/mlng/ml ng/ml TMC278 1 2.12 0.797 0.485 <0.4 0.6 2.13 2.17 TMC278 2 1.400.522 <0.4 <0.4 <0.4 0.539 0.744 TMC278 3 2.42 0.939 0.521 0.405 0.4781.13 1.48 TMC278 4 1.02 <0.4 <0.4 <0.4 0.664 2.19 2.48 compound 1 1 59.16.13 3.36 <2 8.25 22.1 13.1 compound 1 2 26.9 2.54 <2 2.89 <2 6.03 7.25compound 1 3 39.2 4.36 <2 <2 <2 12.3 10.7 compound 1 4 17.3 2.98 <2 <26.27 16.3 15.4

We claim:
 1. A degradable, removable, pharmaceutical subcutaneousimplant for the sustained release of one or more drugs in a subject,comprising a tube that is defined by an outer wall, wherein the outerwall is fabricated from poly(dioxanone); has a plurality of openings onits surface; and completely surrounds a cavity, and wherein the cavitycontains one or more sets of microparticles embedded in a hydrogel,wherein at least one set of the microparticles comprises rilpivirine anda copolymer of lactide and glycolide, and wherein the size of themicroparticles is selected such that the majority of the microparticlescannot pass through the openings.
 2. The implant of claim 1, wherein thecavity contains two or more sets of microparticles.
 3. The implant ofclaim 1, wherein the polymer used to fabricate the microparticles iscopolymers of lactide and glycolide.
 4. The implant of claim 1, whereinthe polymer used to fabricate the microparticles is a copolymer oflactide and glycolide with a mole percent of lactide that ranges from86% to 50%.
 5. The implant of claim 1, wherein at least one set ofmicroparticles comprises a nucleoside reverse transcriptase inhibitor.6. The implant of claim 1, wherein at least one set of microparticlescomprises a nucleotide reverse transcriptase inhibitor.
 7. The implantof claim 1, wherein at least 85% (w/w) of the microparticles are lockedin the cavity of the implant.